Chemokine is known as an endogeneous basic protein having leukocyte chemotactic and activating abilities and strong heparin-binding abilities. At present, it is considered that chemokine is related to not only the control of infiltration of specific leukocyte at the time of inflammations and immune responses but also the development and homing of lymphocyte under physiological conditions and migration of hemocyte precursor cells and somatic cells.
Differentiation, proliferation and cell death of hemocytes are controlled by various types of cytokine. In the living body, inflammations are found topically and differentiation, maturation and the like of lymphocytes are carried out at certain specified sites. That is, various necessary cells migrate into certain specified sites and accumulate therein to cause a series of inflammations and immune responses. Accordingly, migration of cells is also an indispensable phenomenon in addition to differentiation, proliferation and death of cells.
Migration of hemocytes in the living body starts firstly in the development stage by the shift of hematopoiesis started in the aorta-gonad-mesonephros (AGM) region into permanent hematopoiesis in bone marrow via fetal liver. Furthermore, precursor cells of T cells and thymus dendritic cells migrate from the fetal liver into the bone marrow and then into the thymus gland and cytodifferentiate under thymus environment. The T cell which received clone selection migrates into secondary lymphoid tissues and takes part in an immune response in the periphery. The Langerhans' cell of the skin activated and differentiated by capturing an antigen migrates into the T cell region of a topical lymph node and activates naive T cell therein as a dendritic cell. The memory T cell performs its homing again into the lymph node via lymphatic and blood vessels. Also, B cell, T cell in the intestinal epithelium, γδ T cell, NKT cell and dendritic cell migrate from bone marrow without passing through the thymus gland and differentiate to take part in an immune response.
Chemokine deeply takes part in the migration of such various cells. Chemokine receptors are greatly related to the control of inflammation and immune responses through a mechanism in which they are expressed at certain specified periods in variously specific cells and the effector cells are accumulated in a region where chemokine is produced.
For example, it is reported an investigation in animal models such as CCR5-knockout mouse suggesting that CCR5 as a chemokine receptor plays a significant role in rejection in organ transplantation or autoimmune disease, etc. (Transplantation, Vol. 72(7), 1199-1205 (2001); Diabetes, Vol. 51(8), 2489-2495 (2002); Journal of Virology, Vol. 77(1), 191-198 (2003); Journal of Immunology, Vol. 164(12), 6303-6312 (2000)). It is also reported which make a comparison a risk of developing several diseases and a length of the survival of the transplanted graft, etc. between a human having inactive CCR5 and a human having wild-type one (The Lancet, Vol. 357, 1758-1761 (2001); Arthritis & Rheumatism, Vol. 42(5), 989-992 (1999); The Lancet, Vol. 354, 1264-1265 (1999); European Journal of Immunogenetics, Vol. 29(6) 525-528 (2002)). It is suggested that CCR5 is related to several diseases, but they make no reference to the effect of drugs which antagonizes CCR5 in their reports. At present, immunosuppressive treatment for diseases in transplantation area is provided.
That is, a calcineurin inhibitor such as cyclosporin or tacrolimus (FK506) is used mainly with various type of an immunosuppressant agent, for example, a TOR (target of rapamycin) inhibitor such as sirolimus (rapamycin), a non-specific antiphlogistic such as corticosteroids, an antiproliferative drug such as azathioprine, mycophenolate mofetil, etc. However, it frequently causes a chronic rejection or a severe side effect, so it is desired an useful novel immunosuppressant agent which prolongs a length of the survival of the transplanted graft and reduces the side effects in comparison with existing drugs.
An antiinflammatory drug or a drug which modulates immune function such as nonsteroidal antiinflammatory drug (NSAIDs) which have an inhibitory activity against cyclooxygenase (COX), disease modifying anti-rheumatic drug (DMARDs), steroids, etc. is used for treatment for autoimmune disease or allergic diseases. The more effective a drug is, the severer a side effect caused by it is, and it is suggested that the treatment with these drugs is not an underlying remedy for the disease, but a mere symptomatic treatment.
At the same time, acquired immunodeficiency syndrome (hereinafter referred to as “AIDS”) which is induced by human immunodeficiency virus (hereinafter referred to as “HIV”) is one of the diseases of which their therapeutic methods are most earnestly desired in recent years. Once infection with HIV is completed in a CD4-positive cell which is a principal target cell, HIV repeats its proliferation in the body of the patient and, sooner or later, completely destroys T cell which takes charge of the immunological function. During this process, the immunological function is gradually reduced to cause fever, diarrhea, lymph node enlargement and the like various immunodeficiency conditions which are apt to cause complications with pneumocystis carinii pneumonia and the like various opportunistic infections. Such conditions are the onset of AIDS, and it is well known that they induce and worsen Kaposi sarcoma and the like malignant tumors.
As the recent preventive and/or therapeutic methods for AIDS, attempts have been made to, e.g., (1) inhibit growth of HIV by the administration of a reverse transcriptase inhibitor or a protease inhibitor and (2) prevent or alleviate opportunistic infections by the administration of a drug having immunopotentiation activity.
Helper T cells which take charge of the central of immune system are mainly infected with HIV. It is known since 1985 that HIV uses the membrane protein CD4 expressing on the membrane of T cells in the infection (Cell, 52, 631 (1985)). The CD4 molecule is composed of 433 amino acid residues, and its expression can be found in macrophages, some B cells, vascular endothelial cells, Langerhans' cells in skin tissues, dendritic cells in lymphoid tissues, glia cells of the central nervous system and the like, in addition to the mature helper T cells. However, since it has been revealed that the infection with HIV is not completed by the CD4 molecule alone, a possibility has been suggested on the presence of factors other than the CD4 molecule, which are related to the infection of cells with HIV.
CCR5, which is a receptor of RANTES, MIP-1α and MIP-1β, is also used at the time of the infection with a macrophage tropic (R5) HIV (Science, 272, 1955 (1996)).
Accordingly, substances which can compete with CCR5 for HIV, or which can bind to HIV virus thus causing the virus unable to bind to CCR5, could become HIV infection inhibitors.
It is also reported a possibility that the CCR5 is used in the infection with Respiratory Syncytial Virus (hereinafter referred to as “RSV”).
It is reported that CCR5 are expressed in arteriosclerotic plaque, so it is considered that chemokine receptor modulators are also useful in treating cardiovascular diseases.
Based on the above, it is considered that chemokine (for example, RANTES, MIP-1α, MIP-1β, etc.) receptors, especially CCR5 are deeply related to the inflammation, immunological diseases, infectious diseases (infection with HIV, infection with RSV, etc.; and cardiovascular diseases. For example, it is considered that they are related to various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, inflammatory bowel disease such as ulcerative colitis, etc.; immunological diseases (autoimmune diseases, rejection in organ transplantation (rejection of graft of solid organ, rejection of graft of pancreatic islet cells in therapy for diabetes, GVHD (graft-versus-host disease), etc.; immunosuppression, psoriasis, multiple sclerosis, etc.; infectious diseases (infection with human immunodeficiency virus, acquired immunodeficiency syndrome, infection with RSV, etc.; allergic diseases (atopic dermatitis, urticaria, allergic bronchoplumonary aspergillosis, allergic eosinophilic gastroenteritis, etc.; cardiovascular diseases (arteriosclerosis, ischemic reperfusion injury, etc.; acute respiratory distress syndrome, shock accompanying bacterial infection, diabetes mellitus, cancer metastasis and the like.
It is reported that a compound represented by formula (AA):

wherein RAA1 is a hydrogen atom, or an acidic group which may be protected; XAA and YAA each independently represents a bond or a spacer containing 1 or 3 atoms as a main chain; ring AAA and ring BAA may be the same or different and represent a 3- to 15-membered homocyclic, or a heterocyclic group which may have further substituent(s); ring DAA represents a 3- to 15-membered nitrogen-containing heterocyclic group which may have further substituent(s); R2AA represents (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent(s), (3) a cyano group, (4) a hydroxyl group which may be protected, (5) an amino group which may have a substituent(s), (6) an oxo group, (7) a 3- to 15-membered heterocyclic group which may have a substituent(s), or (8) ═N—OR6AA, wherein R6AA a hydrogen atom or a C1-4 alkyl group, a salt thereof or a solvate thereof, or prodrugs thereof is useful as an agent for treatment and/or prevention of CCR5-related diseases (ref. Patent Reference 1).
It is reported that the aminopiperidine derivatives represented by formula (Z):

wherein R1Z is a hydrogen atom or a C1-12 alkyl group; R2Z and R3Z each independently represents a hydrogen atom or a C1-12 alkyl group; XZ is a nitrogen atom or an oxygen atom; and AZ is

wherein R4Z is a hydrogen atom, a C1-12 alkyl group, a C3-8 cycloalkyl group, an aryl group, a substituted aryl group, aryl-C(═O)—, or aryl-CH(OH)—; R5Z is a hydrogen atom, a C1-12 alkyl group, a C1-4 alkoxy group, a halogen atom, or CORZ; and R6Z is a hydrogen atom, a C1-12 alkyl group, or a substituted C1-4 alkyl group as long as the definition of each symbol is an excerpt partially,
are useful as inhibitors of the chemokine receptors (ref. Patent Reference 2).
It is disclosed that the sulfonic acid compounds represented by formula (W):

wherein XW is —O—, —S—, —CH2—or —NR6W; YW is C6-10 aryl or C2-9 heteroaryl; R1W is selected from the group consisting of a hydrogen atom, —OH, a halogen atom, and a C1-8 alkyl group which may be substituted with 1 to 3 fluorine atom(s), etc.; R2W and R3W are selected from the group consisting of a hydrogen atom, oxo group, and a C1-8 alkyl group which may be substituted with 1 to 3 fluorine atom(s), etc.; R4W is selected from the group consisting of a hydrogen atom, —OH, a halogen atom, and —CN, etc.; R5W is a C1-8 alkyl group; aW is 0 to 5; bW is 0 to 2; cW is 0 to 2; and dW is 0 to 4. With the proviso that the definition of each symbol is an excerpt partially,
pharmacological acceptable salts thereof and prodrugs thereof are selective antagonists of CCR1 (ref Patent Reference 3).
Moreover, 1-(4-pyridyl)-piperazine derivatives are described as CCR5 antagonists (ref Patent Reference 4).
On the other hand, it is reported that triazaspiro[5.5]undecane derivatives, quaternary ammonium salts thereof or N-oxides thereof, or pharmacologically acceptable salts thereof regulate the effect of chemokine/chemokine receptor (CCR), so they are useful for prevention and/or treatment of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic diseases (allergic bronchopulmonary aspergillosis or allergic eosinophilic gastroenteritis, etc.), nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, psoriasis, rhinitis, conjunctivitis, ischemic reperfusion disorder, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, cytotoxic shock, diabetes, autoimmune disease, in transplanted organ rejection reactions, immunosuppression, cancer metastasis and acquired immune deficiency syndrome (ref Patent Reference 5).
It is also described that the compounds represented by formula (M):

are modulators of chemokine receptor activity (ref Patent Reference 6).    Patent Reference 1: WO2004/080966    Patent Reference 2: WO02/079186    Patent Reference 3: WO02/102787    Patent Reference 4: U.S. Pat. No. 6,391,865    Patent Reference 5: WO01/040227    Patent Reference 6: WO01/087839